1. Field of the Invention
The present invention relates to a composite pharmaceutical composition for the treatment of metabolic bone disease and the method of preparation thereof, wherein said composition is prepared as a composite pharmaceutical agent comprising calcitriol, alendronate, and adequate amount of other additives. The pharmaceutical composition according to the present invention can inhibit hypercalcemia caused when administered with calcitriol alone, compensate the inhibitory activity of bone remodeling caused by alendronate due to the presence of calcitriol, and also improve drug compliance, thus effectively preventing the occurrence of osteoporosis.
2. Description of the Related Arts
Osteoporosis is a systemic metabolic bone disease characterized by a decrease in bone mass as well as a microstructural change in bone without affecting the chemical composition of bone itself which results in increased susceptibility to bone fractures. In particular, senile patients are known to be more vulnerable to bone fractures, which often result from even minor physical shocks; in fact, approximately 1.3 million out of 25 million osteoporosis patients in the U.S. are known to suffer from bone fractures each year, which accounts for almost 10% of total U.S. population.
Osteoporosis can be divided into type I and type II. Type I osteoporosis occurs most frequently in postmenopausal women and is characterized by having a marked increase of bone resorption due to deficiency of estrogen. It is very marked increase of bone resorption due to deficiency of estrogen. It is very common to observe type I osteoporosis patients lose trabecular bone and this causes frequent fractures of spines or wrists. Meanwhile, type II osteoporosis usually occurs in elderly people or in males and is characterized by a drastic decrease in bone remodeling capability rather than an increase in bone resorption. However, the increase in bone resorption as well as the decrease in calcium absorption by osteoclasts are known to be common to both types of osteoporosis.
Therapeutic agents employed in treating osteoporosis in clinical fields are generally divided into two groups; a group that can expedite bone remodeling and another that can prevent bone resorption. The examples of active therapeutic agents that can promote fast bone remodeling include anabolic steroids, fluoride, vitamin D and parathyroid hormones. With the recent introduction of the mechanism of bone formation, vitamin D derivatives have been the object of the public attention because of their roles in mediating balanced bone mass. Calcitriol, being one of the active vitamin D3 derivatives expressed as 1,25-(OH)2 D3, is one of the above-mentioned bone remodeling activators, and is also a hormone which enables to prevent osteoporosis because it can not only increase calcium absorption from the intestinal tract but also can inhibit the decrease of bone mass. However, calcitriol is also shown to cause hypercalcemia when used alone. Hypercalcemia, a metabolic disease characterized by having a plasma calcium concentration of 11.0 mg/dL or above in blood, is one of the most common life-threatening disease closely associated with fatal disease such as a tumor. In fact, calcitriol induces an increase of calcium concentration in blood as well as the abnormal control of calcium concentration by bone metabolism thus resulting in hypercalcemia. The symptoms of hypercalcemia or calcium addiction (a severe case of hypercalcemia with prolonged duration) due to side effects of calcitriol and overdose of vitamin D are very similar to that shown in hypercalcemia. Hypercalcemia occasionally entails acute symptoms such as anorexia, headache, emesis, constipation, and chronic symptoms of hypercalcemnia include dystrophy, paresthesia, pyrexia with thirst, hyperurisis, dehydration, acedia, groweighth retardation, urinary infection, etc. Patients with hypercalcemia often experience to have complications and this adds difficulty in treating disease such as osteoporosis.
The conventional pharmaceutical agents used in treating osteoporosis as bone resorption inhibitors include estrogen, calcitonin, bisphosphonate and ipriflavone.
Japanese Patent Publication No. 7-330613 discloses a bone remodeling activator, which contains alendronate, a kind of bisphosphonates, as an active agent and can activate the calcification of osteoblasts as well as the formation of bone matrix in the presence of dihydroxy vitamin D3.
French Patent Application No. 884628 discloses a pharmaceutical agent for oral administration which uses bisphosphonate as a substrate and contains an adequate amount of sodium lauryl sulfate.
Application Ser. No. 09/125,372 discloses enteric coated tablets that contain bisphosphonates.
However, the above-mentioned bone resorption inhibitors have not been successful in sufficiently improving the bone mass of patients with already progressed osteoporosis and thus there has been along-awaited need for the development of very effective bone remodeling activators.
A recent Italian report discloses a method of combined administration of both alendronate and calcitriol [Clinical Drug Investigation (1998) March, 15(3), 235-244]. In this report, alendronate and calcitriol were not administered as a composite tablet but were administered independently. For example, alendronate was administered once a day while calcitriol was administered twice a day with a certain timely interval allowed between each administration.
Furthermore, the alendronate must be administered before meals because the pharmaceutical effect was shown much decreased due to poor absorption when they were taken after meals.
Considering that most osteoporosis patients are elderly people and that most of them also take various kinds of drugs daily, it appears very plausible that the patients often forget to take one or two drugs that they are supposed to take because of the rather complicated nature of administration of the above drugs and thus the effects of slid administration also remain questionable.
Alendronate can cause a local stimulation on mucous membranes at the upper gastrointestinal tract and this often results in a few side effects in esophagus such as esophagitis, esophageal ulcer, esophageal erosion. Therefore, it becomes necessary for patients to take in sufficient amount of water when they take a drug containing alendronate so that the drug they are taking can pass through the esophagus as promptly as possible and thus keeping esophageal stimulation to the minimal level. And his has been also raised as a burden to most patients that lowers drug compliance.
In the Conference of Japanese and American Glaucoma Societies"" held in Vancouver, Canada in January 1997, it was announced that the final goal of developing composite pharmaceutical agents was to improve drug compliance. In the xe2x80x98Fifth Conference on Retroviruses and opportunistic infectionxe2x80x99 which was held in Chicago on Feb. 4, 1998, it was shown that the effect of Combivir, a composite pharmaceutical agent containing both lamivudine and zidovudine wherein the pharmaceutical mechanisms differ from each other, had an improved therapeutic effect of 96% as compared to 72% of effect obtained when lamivudine and zidovudine were administered independently as a separate drug, respectively, and here the improvement in therapeutic effect is speculated to be due to the improvement in drug compliance of the patient to the composite pharmaceutical agent.
There have been no studies conducted on the therapeutic treatment of osteoporosis with respect to preparation of composite tablets containing both calcitriol and alendronate, and instead there have been many lines of studies focused on the effect of alendronate as a therapeutic agent treating hypercalcemia caused by vitamin D intake. Therefore, it is in high demand to develop composite pharmaceutical agents with advanced formulation technologies for the treatment of osteoporosis which can not only minimize side effects such as hypercalcemia, caused when calcitriol was administered alone, but can prevent/treat osteoporosis with a little dose and enhance drug compliance, which is usually low in conventional drugs, by remedying the rather complicated way of administration and preventing esophageal side effects.
The present invention relates to a pharmaceutical composition for the treatment of metabolic disease and the method of preparation thereof, and more particularly, to an improved pharmaceutical composition for the therapeutic treatment of metabolic disease and the method of preparation thereof, wherein said composition is prepared as a composite pharmaceutical agent comprising (a) calcitriol; which reduces the rate of spine fractures and increases bone density; (b) alendronate, a bone resorption inhibitor, as active ingredients in an optimal mixing ratio to exert the greatest therapeutic effect; and (c) adequate amount of additives such as resorption fortifier of alendronate, so that the resulting composition can reduce hypercalceria caused by calcitriol, compensate the inhibitory activity of bone remodeling caused by alendronate due to calcitriol, improve drug compliance usually accompanied because of the difficulty in administration and the usual side effects in esophagus, thus effectively preventing the occurrence of osteoporosis.